The overall hypothesis of the Triglycerides, Diabetes and Cardiovascular Disease Program Project is that abnormal metabolism of triglyceride-rich lipoproteins driven by specific proteins?APOC3, ANGPTL3, PLTP, and LPL?promotes the accumulation of highly atherogenic remnant lipoprotein particles in patients with diabetes, even in those with normal triglyceride levels. Remnant lipoprotein particles and associated abnormalities in HDL contribute to cardiovascular disease risk by altering macrophage functions, thereby promoting atherogenesis and increasing cardiovascular disease risk in diabetes. We propose that the increased risk of cardiovascular disease (CVD) associated with diabetes can be understood, prevented, and treated only by increasing our knowledge of the factors that regulate triglyceride- rich lipoproteins (TRLs) and their remnant lipoprotein particles (RLPs) and associated macrophage phenotypes. TRLs and their remnants comprise a great variety of nascent and metabolically derived particles differing in size, protein composition, and lipid content, which has made it difficult to identify the mechanisms that promote atherosclerosis. We plan to address this complexity by focusing on specific pathways and proteins and by using unique analytical tools. We believe that a highly interactive and interdisciplinary group of investigators with extensive expertise in this area, such as ours, is needed to answer the question of how TRLs and RLPs promote CVD risk. The expertise of our team in different aspects pertaining to the overall hypotheses of this Program Project will ensure synergy and cross-fertilization between Projects, which is likely to markedly advance research in this important and timely area. Importantly, the RLPs and proteins that control them are amenable to therapeutic intervention. We therefore believe that our projects will provide new insights into the pathogenesis of CVD in diabetes and suggest new ways to target and prevent the increased CVD risk in this large population. The Program Project Grant consists of four Projects and three Core units: ? Project 1: Diabetes, triglyceride-rich lipoproteins, and advanced atherosclerosis ? Karin E. Bornfeldt, PhD, Project Leader ? Project 2: Regulation of lipid and glucose metabolism by ANGPTL3 in humans ? Nathan Stitziel, MD, PhD, Project Leader ? Project 3: Lipolysis regulation and diabetes-impaired regression ? Ira J. Goldberg, MD, Project Leader ? Project 4: Lipoproteins and CVD risk in diabetes ? Jay W. Heinecke, MD, Project Leader ? Core A: Administrative Core ? Karin E. Bornfeldt, PhD, Core Director ? Core B: Proteomics and lipoprotein characterization core ? Tomas Vaisar, PhD, Core Director ? Core C: Myeloid cell and atherosclerosis core ? Jenny E. Kanter, PhD, Core Director